Soft tissue sarcoma

Factsheet

Definition of soft tissue sarcomas

  • It describes a group of malignant tumours that originate in “soft tissues”. Soft tissues include muscles, tendons, fat, blood and lymph vessels, nerves and joint linings (synovial tissue).
  • As soft tissues are found everywhere in the body, soft tissue sarcomas may arise in any part of the body.

Diagnosis

  • Unfortunately, sarcomas can be asymptomatic for a long time and the symptoms will depend on the part of the body which is affected. Sarcomas can be suspected when a lump appears on a leg, an arm or the trunk.
  • Radiological examinations are mandatory to determine the extent of a soft tissue sarcoma and to establish the presence or absence of distant metastasis.
  • A sample of the tumour (biopsy) must be obtained for analysis in the laboratory to confirm the diagnosis and get more details about the type of sarcoma.

Treatment

  • Localised sarcomas are confined to the primary site and have not spread to nearby tissues or to other areas of the body.
    • Removal of the tumour by surgery is the standard treatment
    • Radiotherapy and chemotherapy, either alone or in combination after surgery, can sometimes be used to increase the chance of definitive cure or reduce the risk that the tumour comes back.
    • Radiotherapy can be used before surgery to shrink the size of the tumour and allow it to be removed completely
  • Advanced sarcomas have spread from where they started to other parts of the body. This is known as metastatic or advanced cancer.
    • The main treatment approach is the use of chemotherapy and molecularly targeted therapy. The choice of the drugs will mainly depend on the clinical conditions of the patient and on the type of sarcomas.
    • Radiotherapy either during or after chemotherapy could be used to relieve symptoms and control metastases.
    • Surgery may be used to relieve symptoms or to cure the cancer in some specific cases.

Follow-up

  • Follow-up appointments include physical examination, blood tests and radiological examination; they will be done for several years.
  • The optimal time schedule for follow-up for soft tissue sarcomas is unknown and depends on the location, the size and the aggressiveness (grade) of the tumour. Follow-up after treatment for high or intermediate grade soft tissue sarcoma is more intensive than for low grade sarcoma.

Introduction

Definition of soft tissue sarcomas

Soft tissue sarcomas are a diverse group of malignant tumours that originate when abnormal cells grow out of control in “soft tissues” and “connective tissues”. Soft tissues can be found in any part of the body and include muscles, tendons, fat, blood and lymph vessels, nerves and joint linings (synovial tissue). The type of sarcoma depends on the kind of cells it arises from. Connective tissues include all tissues that support, connect or separate different tissues in the body. Therefore it can be found in the structure of organs in the body (e.g., the uterus). Soft tissue sarcomas, therefore, can grow almost anywhere, but are most common in arms and legs (50%), followed by trunk and abdomen (40%), and head and neck (10%).

Important note regarding other types of sarcomas

Kaposi sarcomas and gastrointestinal stromal tumours (GIST) are soft tissue sarcomas which are treated differently than the other soft tissue sarcomas and therefore are not covered in this guide.
Bone sarcomas arise from cells making the bones and are also called osteosarcomas. Ewing’s sarcoma is a rare type of sarcoma usually also arising in the bone. Bone and Ewing’s sarcomas are treated differently than soft tissue sarcomas and therefore are not covered in this guide.

 

PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
This guide for patients has been prepared by the Anticancer Fund as a service to patients, to help patients and their relatives better understand the nature of soft tissue sarcomas and appreciate the best treatment choices available according to the subtype of soft tissue sarcomas. We recommend that patients ask their doctors about what tests or types of treatments are needed for their type and stage of disease. The medical information described in this document is based on the clinical practice guidelines of the European Society for Medical Oncology (ESMO) for the management of soft tissue sarcomas. This guide for patients has been produced in collaboration with ESMO and is disseminated with the permission of ESMO. It has been written by a medical doctor and reviewed by two oncologists from ESMO including the leading author of the clinical practice guidelines for professionals. It has also been reviewed by patient representatives from ESMO’s Cancer Patient Working Group.

Frequency

Are soft tissue sarcomas frequent?

Soft Tissue Sarcomas are rare tumours. In Europe, 4 to 5 cases will be diagnosed among 100,000 people every year, with no major difference between countries. The lifetime risk of developing a soft tissue sarcoma is about 0.15-0.50%. Soft tissue sarcomas are more common in adults than in children and the peak incidence is around the age of 50-60, but the tumour can occur at any age.
Because of their rarity and the frequent need of multimodal treatment, management of soft tissue sarcomas should be carried out in reference centres with expertise in the treatment of this cancer, involving dedicated pathologists, radiologists, surgeons, orthopaedists, radiation oncologists, medical oncologists and paediatric oncologists.

Causes

What causes soft tissue sarcomas?

It is not clear why soft tissue sarcomas occur. However, some risk factors have been identified. A risk factor increases the risk of cancer occurring, but it is neither necessary nor sufficient to cause cancer. A risk factor is not a cause in itself.
Some people with these risk factors will never develop a soft tissue sarcoma and some people without any of these risk factors may nonetheless develop this cancer.

The main risk factors for soft tissue sarcoma are the following.

  • Genetic predispositions: both inherited and acquired conditions may be associated to a soft tissue sarcoma.
    • Li-Fraumeni syndrome is an inherited genetic condition due to the mutation of a tumour suppressor gene (p53), i.e., a gene which helps protect cells from cancer. Patients with this rare syndrome are more prone to develop several type of cancers, including soft tissue sarcomas.
    • Familial Adenomatous Polyposis is a condition characterised by mutations in the APC (adenomatous polyposis coli) gene, which is a tumour suppressor gene. Families affected by familial adenomatous polyposis develop hundreds to thousands of colonic polyps that most often arise from the second decade of life. Colonic polyps are benign tumours which can evolve to colon cancer. There is also a high frequency of intra-abdominal desmoid tumours (a type of soft tissue tumours) among patients with familial adenomatous polyposis.
    • Gardner’s syndrome is a type of familial adenomatous polyposis associated with the development of other benign tumours such as osteomas, epidermal cysts, and fibromas. There is a high frequency of intra-abdominal desmoid tumours (a type of soft tissue tumours) among patients with Gardner's syndrome.
    • RB (retinoblastoma) syndrome is a familial syndrome characterised by an alteration of the RB gene, which is a tumour suppressor gene. Patients usually develop malignant tumours of the retina in both eyes during infancy. Sarcomas of soft tissue and bone may develop later in life.
    • Neurofibromatosis I (von Recklinghausen’s disease): this inherited disease is genetically characterised by a mutation in the NF1 gene, which is a tumour suppressor gene. Clinical features include the presence on the skin of multiple, widespread benign tumours known as neurofibromas, and of café-au-lait spots. Patients with Von Recklinghausen's disease have an increased risk of developing malignant peripheral nerve sheath tumours (MPNST) and, to a lesser extent, gastro-intestinal stromal tumours (GISTs) and rhabdomyosarcomas.
    • Neurofibromatosis II: this syndrome is caused by mutations to the tumour suppressor gene NF2. It is typically associated with schwannomas of the acoustic nerve in ear(s) or other nerves. There is a predisposition to meningiomas and gliomas, two types of tumour developing from cells of the nervous system.
    • Other genetic conditions such as Basal cell nevus syndrome, Tuberous sclerosis, and Werner's syndrome are associated with an increased risk of developing a soft tissue sarcoma.
  • Ionizing radiations: exposure to ionizing radiations can increase the risk of soft tissue sarcomas even in the absence of other risk factors. Sarcomas can rarely arise following exposure to radiation given to treat other cancers, like breast cancer or lymphoma. In these cases the sarcoma mostly starts in the area of the body that had been treated with radiation. The frequency increases with the treatment dose and decreases with age. The average time between radiation exposure and diagnosis of a sarcoma is about 10 years. Radiation exposure is, however, a very rare cause of soft tissue sarcomas.
  • Chemical agents: many chemical carcinogens have been put forward as risk factors of soft tissue sarcoma, though few of these associations have been clearly established. There is an association between exposure to vinyl chloride or arsenic and hepatic angiosarcoma (a type of soft tissue sarcoma) and between exposure to phenoxy herbicides or dioxins and soft tissue sarcoma in general. Occupational exposure carries the highest risk.

Diagnosis

How are soft tissue sarcomas diagnosed?

Sarcomas often do not cause symptoms for a long time, until they become quite large and press on an organ, a nerve or a muscle. They may arise in any part of the body and the symptoms will depend on the part of the body that is affected. The main circumstance is when a lump appears on the leg, arm or trunk. They may also be found during an investigation of other symptoms or during a routine operation.

The diagnosis of sarcoma is based on the following examinations:

  1. Medical History and Clinical Examination. Your doctor will begin by taking your complete medical history, asking when the symptoms began and how they have changed over time and check for risk factors. Your doctor will then perform a complete physical examination, including the area where there is the lump and/or pain. If the sarcoma is in any part of arm or leg, the most common symptom is an uncomfortable swelling. Occasionally, this swelling may be painful or tender, but it may also be painless. If the sarcoma is in the central part of the body (the trunk), the symptoms will depend on which organ is affected. For example a sarcoma in lung may cause breathlessness and cough; a lump in abdomen could cause abdominal pain, vomiting and constipation; a sarcoma affecting the womb could cause uterine bleeding and pain in the lower part of the abdomen, occurring outside of menstrual periods or after menopause.
     
  2. Blood Test. A blood sample is performed to check your general health status, and to explore the function of the liver, kidneys and blood cells.
     
  3. Radiological examination. A wide range of imaging techniques is used to look inside the body to determine the extent of a soft tissue sarcoma and establish the presence or absence of distant metastatic disease.
  • Chest X-ray: a plain chest X-ray could be done to determine whether the sarcoma has spread to the lungs, as this is one of the most common sites it may spread to.
  • Ultrasonography: a type of examination that uses sound waves and their echoes to create images from within the body. There are different kinds of ultrasound scans depending on which part of the body is being examined and why. An external ultrasound may be used to examine the liver, kidneys, and other organs in the abdomen and pelvis, or heart function. An ultrasound probe placed into vagina allows a doctor to look at the womb. Endoscopic Ultrasound Scan (EUS) uses a tube-like instrument called endoscope with an ultrasound scanner attached; it uses sound waves to produce pictures of abdominal organs.
  • CT scan: a Computerised Tomography scan is an X-ray technique that produces detailed pictures of the inside of the body. You may be asked to drink a liquid called oral contrast and you may also receive an intravenous contrast dye to help the organs or tissues show up more clearly.
  • PET scan: Positron Emission Tomography is mainly used to find out if the sarcoma has spread to other parts of the body. It uses a substance that contains glucose, which is injected into the patient.This radiolabeled  glucose-based substance is absorbed by cancerous cells which are less able to eliminate it than normal tissues so that it remains “trapped” in cancerous tissues. PET scans can also be used to examine the effect of the treatment on tumours.
  • MRI: Magnetic Resonance Imaging uses magnetic fields and radio waves to create a series of detailed pictures of the tissue of the body. MRI is able to show more clearly soft tissues than other types of scan. It is often used for tumours of the limbs.
  • Bone scintigraphy: a type of scan using a radiolabelled substance to find out whether the sarcoma has spread to the bones. The radiolabelled  substance travels to areas of bone changes, which appear brighter and indicates possible spread of the tumour.
  1. Histopathological examination. Histopathologic exam is made on a biopsy or a piece of tissue after excision of the whole tumour by surgery. Only the histopathologic assessment of the tumour will disclose whether the tumour is a soft tissue sarcoma, and the type of sarcoma. It will also provide the “malignancy grade”, i.e., a score of the aggressiveness of the cells making the tumour. Grades are explained in more details further in the text.

A biopsy takes a sample of the tumour, which will be examined under a microscope to look for cancer cells. Different types of biopsies may be used: core needle biopsy, excisional biopsy and open biopsy.

  • Core needle biopsy: a sample of cells or part of a lump is removed using a needle. Before the biopsy is taken, a local anaesthetic is injected to numb the area and several samples may be taken. If the lump is deep within the body the doctor may use an ultrasound or a CT scan to guide the needle into the right place.
  • Incisional / Excisional biopsy: under anaesthesia, a surgical knife is used to remove a tissue sample from the lump (“incisional”), or the entire tumour (“excisional”). This is the most practical option for rather small sarcomas near the surface of the body (<5cm superficial lesions).
  • Open biopsy: a surgical knife is used to open the area and remove a tissue sample from the lump or the entire tumour; it may be done under a local or general anaesthesia, depending on the position and depth of the tumour.

Treatment

What is important to know to get the optimal treatment?

Doctors will need to consider many aspects of both the patient and the cancer in order to decide on the best treatment.

Relevant information about the patient
  • General well‐being
  • Personal medical history
  • History of cancer in relatives
  • For women, status regarding menopause, which in some cases requires taking a blood sample to measure the level of some hormones in the blood
  • Results from the clinical examination by the doctor
  • Results from blood tests performed to assess the white blood cells, the red blood cells and the platelets, and tests performed to exclude any problems in the heart, liver, and kidneys.
Relevant information about the cancer
  • Results of the biopsy

The sample of tumour obtained through biopsy will be examined in the laboratory. This examination is called histopathology. The second histopathological examination involves the examination of the whole tumour after surgical removal. It is very important to confirm the results of the biopsy and to provide more information on the cancer. Results of the examination of the biopsy should include:

  • Histological type: Soft tissue sarcomas include several dozen different histologic subtypes. It is strongly recommended that the examination of the biopsy and of the tumour is done by an expert pathologist from a reference centre. The most common sub-types of soft tissue sarcoma in adults include:
    • Undifferentiated (or unclassified) pleomorphic soft tissue sarcoma, although rare, it is the most frequent sarcoma in adult life. It can arise in any part of the body but most commonly in the leg, especially in the thigh.
    • Liposarcoma arises from cells storing the fat in deep soft tissue. It can occur in almost any part of the body, but more than half of liposarcoma cases involve the thigh, and up to a third involve tissue in the abdomen.
    • Leiomyosarcoma arises from cells in a type of muscle tissue called smooth muscle. Smooth muscles are found in the walls of organs like the heart and stomach, as well as in the walls of blood vessels. This means it can develop anywhere in the body, but most common places are the walls of the womb (uterus), the limbs, and the stomach.
    • Synovial sarcoma usually occurs near to the main joints of the arms, legs, and neck.
    • Malignant peripheral nerve sheath tumour (MPNST) arises from connective tissue surrounding the nerve. They are also called neurofibrosarcoma or malignant schwannoma.
    • Angiosarcoma arises in the structures of the inner lining of blood vessels and can occur in any area of the body. Most commonly, it occurs in the skin, breast, liver, spleen, and deep tissue.
    • Solitary fibrous tumour (SFT) mostly involves the pleura.
    • Dermatofibrosarcoma Protuberans (DFSP) develops in the deep layers of skin and is most commonly found on the torso, but also on the arms, legs, head and neck areas.
    • Desmoplastic small round cell tumour (DSRCT) occurs in adolescents and young adults and generally has an aggressive course. Clinical manifestations are often related to widespread abdominal disease.
    • Rhabdomyosarcoma arises from cells making the skeletal muscles, the muscles one can voluntarily control. However, rhabdomyosarcoma can also start from cells making the muscles nearly anywhere in the body, even in parts/organs that normally lack skeletal muscles. The most common places for rhabdomyosarcoma include the head, neck, bladder, vagina, arms, legs, and trunk of the body. Very rarely, rhabdomyosarcoma develops in the prostate gland, in the middle ear, or in the bile ducts.

Desmoid tumours, also called deep or aggressive fibromatosis, are rare tumours which are not formally sarcomas. They are usually grouped together with soft tissue sarcomas because they arise from fibroblasts, which are cells found throughout the body providing support and protection to organs such as lung, liver, blood vessels, heart, kidneys, skin, bowels etc. Desmoid tumours can arise in virtually any part of the body. Treatment principles for desmoid tumours are described in this guide for patients.

  • Grade: The grade of a tumour indicates how “aggressive” the tumour looks when analysed under a microscope by a doctor called a pathologist. In soft tissue sarcomas, it considers how closely the tumour resembles normal tissue (differentiation), how many of the cells appear to be dividing (mitotic count), and how much of the tumour is made up of dying tissue (necrosis). The Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system is generally used, which distinguishes three malignancy grades based on differentiation, necrosis, and mitotic rate. Based on these 3 characteristics, tumours are classified into grade 1 (low), grade 2 (intermediate) and grade 3 (high) tumours. The lower the grade, the better the prognosis.
  • Molecular profiling: Additional information about the characteristics of the tumour may be asked. This relies on examination of structures (such as chromosomes or genes) and molecules (such as proteins) of the cells. These analyses may be performed either to confirm or clarify the histological type of soft tissue sarcoma, to provide additional information about the prognosis of the disease, or to help making decision about the treatment, especially with regard to the use of targeted therapies, therapies that work by binding to a specific protein or structure of the cells and thereby inhibiting their function.

Doctors use staging to assess the extension of the cancer in the body, which is an important determinant of prognosis. The most widely used staging system for soft tissue sarcomas is the TNM system. The combination of T, size of the tumour and invasion of nearby tissue, N, involvement of lymph nodes, and M, metastasis or spread of the cancer to other organ of the body, will classify the cancer into one of the following stages. For soft tissue sarcomas, the TNM staging takes also into account the malignancy grade (G), which in soft tissue sarcomas is a very important prognostic factor.
The stage is fundamental in order to make the right decision about the treatment. The lower the stage, the better the prognosis.

The table below presents the different stages for soft tissue sarcomas. The definitions are somewhat technical, so that it is highly recommended to ask doctors for more detailed explanations.

Stage Defenition
Stage IA

The tumour

  • is categorised as grade 1;
  • is no more than 5 cm its greatest dimension;
  • has not spread to lymph nodes or to other parts of the body.
Stage IB

The tumour

  • is categorised as grade 1;
  • is more than 5 cm in its greatest dimension;
  • has not spread to lymph nodes or to other parts of the body.
Stage IIA

The tumour

  • is categorised as grade 2 or grade 3;
  • is no more than 5 cm in its greatest dimension;
  • has not spread to lymph nodes or to other parts of the body.
Stage IIB

The tumour

  • is categorised as grade 2;
  • is more than 5 cm in its greatest dimension;
  • has not spread to lymph nodes or to other parts of the body.
Stage III

The tumour

  • either is categorised as grade 3 and more than 5 cm in its greatest dimension but has not spread to lymph nodes or to other parts of the body;
  • or has spread to lymph nodes, irrespective of its size and grade.
Stage IV

Irrespective of its size and grade, the tumour has spread to other part(s) of the body (metastasis).

 

What are the treatment options?

Planning of the treatment involves a multidisciplinary

team of medical professionals with a high level of experience in the management of these tumours (usually called reference or expert centres). This usually implies a meeting of different specialists, called multidisciplinary opinion or tumour board review. In this meeting, the planning of treatment will be discussed according to the relevant information mentioned before.

The treatment will usually combine therapies that:

The extent of the treatment will depend on the stage of the sarcoma, on the characteristics of the tumour and on the risks for the patient.

Treatments have their benefits, their risks and their contraindications. It is recommended that patients ask their doctors about the expected benefits and risks of every treatment in order to be informed about the consequences of the treatment. For some treatments, several possibilities are available and the choice should be discussed according to the balance between benefits and risks.


Treatment plan for localised disease

Soft tissue sarcomas are localised when they are still confined to the primary site and have not spread to nearby tissues or to other areas of the body. At this stage, the main therapeutic goal is to remove the whole tumour by surgery whenever possible. Radiotherapy and chemotherapy can also be used to increase the chance of definitive cure or to reduce the risk that the tumour comes back.

Treatment for localised form of soft-tissue sarcomas includes therapy options that aim to act locally in the region affected by disease.

Surgery

Most frequently, surgery is the standard treatment method used for localised sarcoma. As soft tissue sarcomas are rare, surgery should be performed by a surgeon who specialises in treating them. The goal of most sarcoma surgery is complete resection without leaving anything behind (microscopically negative margins), thereby reducing the risk of local recurrence.
The completeness of the surgical resection can be defined by several terms:

  • "R0" resection means complete removal of all tumour according to the analysis of the tissue margins by microscope done by the pathologist;
  • "R1" resection indicates that the margins of the resected parts show presence of tumour cells when viewed microscopically;
  • “R2" resection indicates a macroscopical residual disease (a portion of tumour visible to the naked eye).

Small sarcomas can usually be effectively removed by surgery alone. R1 and R2 margins may need additional treatment by surgery; other options are to treat the resected margin containing tumour cells with radiation and possibly chemotherapy.

Radiotherapy

High grade, deep seated tumours larger than 5 cm are often treated with a combination of surgery and radiation therapy; radiation therapy may be used before (neo-adjuvant) surgery (to shrink the tumour size and allow it to be removed completely) or after (adjuvant) surgery (to kill any remaining cancer cells); re-operation may be considered in case of positive margins.

Chemotherapy

There is no consensus over the current role of chemotherapy for patients who have a localised disease. Chemotherapy may be considered alone or in combination with radiotherapy before or after surgery in selected cases. It may especially be considered in these 2 situations:

  • When the disease is considered to be at high risk of recurrence (i.e. high grade, deep seated, > 5 cm). In this case, the goal is to reduce the risk of distant recurrence, while possibly exerting a local benefit as well. In these cases, using regional hyperthermia together with chemotherapy has been shown to extend survival without the disease coming back. Regional hyperthermia uses a machine placed around the area to be treated. The machine will heat the area for 60 minutes at a temperature of around 42°C. Heat kills tumour cells directly, increases efficacy of the chemotherapy drugs, and induces an immune response towards the tumour.
  • When the disease is localised but cannot be resected at all or when the resection is incomplete because part of the tumour could not be removed (positive margins). It may indeed not be possible to remove a tumour completely for several reasons, including its size or its location in an area considered as too risky for surgical removal (involvement of major blood vessels, nerves, etc.). It could also be because of other health conditions that could increase the risk of surgery

Today, it is rare to resort to amputations for limb sarcomas because currently it is often possible to remove just the cancer and some of the tissues around it using a conservative approach, known as “limb-sparing” surgery, possibly with the contribution of other treatment modalities, including radiotherapy and chemotherapy.
In a few selected cases, a procedure known as isolated hyperthermic limb perfusion can be proposed. It is a surgical technique aiming at injecting high-dose of chemotherapy in the affected arm or leg, which has been previously heated to a temperature of about 41°C to make cancer cells more sensible to the effect of chemotherapy. This technique requires temporary deviation of the blood circulation to and from the limb using surgery. With this technique, a high concentration of chemotherapy can be obtained in the limb with very limited diffusion to the rest of the body. This model of therapy is complicated and is restricted to centres experienced in this technique.


Treatment plan for advanced disease

Soft tissue sarcomas are advanced when they have spread from where they started to other parts of the body. This is known as metastatic cancer. At this stage, the main therapeutic goal is to control it, leading to a better quality of life by improving symptoms.

There is no “one” advanced disease and deciding about the best treatment strategy requires careful consideration of the different options by a multidisciplinary team.

Occasionally, surgery may be considered in metastatic disease to relieve symptoms and to cure the cancer in some specific cases, mainly when lung metastases are relatively few, slowly growing, and are not accompanied by extra-pulmonary lesions.

Radiotherapy may also be given to relieve symptoms and control metastases, in particular bone metastases.

However, the main treatment approach in case of advanced disease is the use of systemic therapy, which includes both chemotherapy and molecularly targeted therapy. Each type of drug works differently, but all alter the way a cancer cell grows, divides and repairs itself.

Chemotherapy

Chemotherapy is the mainstay of the treatment of advanced disease, as the drugs administered enter the bloodstream and reach cancer cells throughout the body. The most commonly chemotherapeutic drugs used in soft tissue sarcomas are doxorubicin and other anthracyclines, ifosfamide, trabectedin, gemcitabine, docetaxel and paclitaxel.

These drugs can be given alone or in combination, and may be given as an outpatient or as an inpatient* with admission to hospital for a few days. Chemotherapy is given in cycles of treatment and the chemotherapy regimen usually consists of a number of cycles given over a set period of time: the number of cycles depend on the type, site and size of sarcoma and how it is responding to the drugs.

Chemotherapy in patients with advanced disease should be based on doxorubicin or epirubicin (both drugs belonging to the same ‘family’ and called anthracyclines). In patients with angiosarcoma, paclitaxel (or docetaxel) can be proposed in place of doxorubicin.

Adding other drug(s) to doxorubicin or epirubicin can allow a greater shrinkage of the tumour in some patients. This choice primarily depends on the histological type of the cancer, as types known to be sensitive to chemotherapy will shrink more when a combination of drugs is used. In the majority of cases, ifosfamide is preferred to be used in combination with doxorubicin or epirubicin. Dacarbazine combined with doxorubicin is however preferred for patients with leiomyosarcoma or solitary fibrous tumour.

If the first chemotherapy administered did not help, another chemotherapy may be proposed even though the evidence for a benefit remains limited. The choice of the drug(s) will depend on the drug(s) already received as well as on the tumour histological type. Drugs that can be considered includes ifosfamide, trabectedin, gemcitabine, docetaxel and paclitaxel.

Targeted therapy

Targeted therapy may also be used. These therapies work by binding to a specific protein or structure involved in tumour growth and progression. Side effects are different from the side effects of the traditional chemotherapy, and depend on the mechanism of action of the drug. The targeted drugs approved for the use in soft tissue sarcomas in Europe are:

  • Pazopanib (in soft tissue sarcomas other than liposarcomas)
  • Imatinib (in dermatofibrosarcoma, when it requires a systemic therapy)

There is anecdotal evidence in favour of the use of other targeted therapies for patients with some rare specific tumour types. It is recommended to ask doctors about these options.

Radiation therapy

Radiation therapy may be considered to relieve symptoms or prevent complications, for example in the case of bone metastases.

Surgery

Surgery of metastases may be considered depending on their location and on the history of the disease. For example, this would be the case when lung metastasis appears a long time after initial treatment and when, the surgeon considers it can be completely removed.
 

Why are clinical trials important?

Clinical trials try to find new treatments for cancer and find out if new cancer treatments are safe and effective or better than the standard treatment. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive new therapy options. The purpose of clinical trials also includes testing new ways to stop cancer from recurring, reducing the side effects of cancer treatment, and looking for better ways to prevent, screen or diagnose a tumour. Trials help to extend knowledge about cancer, improve current treatment and develop new treatments, now and for future patients. You are encouraged to ask whether there are any clinical trials in which you could be enrolled.

Special clinical presentations and soft tissue sarcoma entities

The management of some very rare sarcomas varies from the general management of the soft tissue sarcomas described until now. These differences are explained below.

Retroperitoneal sarcoma
Some sarcomas arise in the retroperitoneum, which is the space between the abdominal wall and the peritoneum - a membrane that forms the lining of the abdominal cavity and covers most of the intra-abdominal organs. Retroperitoneal sarcomas most commonly present as an abdominal mass and can grow very large without causing symptoms. The most common early symptoms leading to a discovery of a retroperitoneal sarcoma are feeling full quicker than usual when eating, pain in the abdomen, bleeding, gastrointestinal obstruction, or oedema of the legs.
Special care should be taken for the diagnosis of retroperitoneal sarcomas, especially in terms of imaging and ways of obtaining a sample of the tumour (biopsy). For these reasons, it is crucial that these steps are undertaken in a centre with experience in soft tissue sarcomas and that results of the imaging and biopsy are discussed by a multidisciplinary team.
Surgery is the standard treatment of a retroperitoneal sarcoma. Resection of organs in the abdomen is often required and complete resection margins may be difficult to achieve due to the complexity of the anatomy in this part of the body. Administering chemotherapy, radiotherapy, regional hyperthermia or combinations before surgery may be considered after careful discussion, especially when it is expected that the treatment will reduce the size of the tumour and therefore allow a complete surgical resection.
Although not standard, chemotherapy and radiotherapy may also be considered after the operation but seems however of limited benefit in most patients.

Uterine sarcoma
Uterine sarcoma is a tumour in which malignant cells form in the muscles of the uterus or other connective tissues that support the uterus. Types of tumours include leiomyosarcomas, endometrial stromal sarcomas and undifferentiated sarcoma, based on the type of cell from which they originally developed. Carcinosarcomas (also called malignant müllerian mixed tumours) are currently considered as cancer originating from epithelial tissue and are treated as endometrial cancers. Common symptoms are pain or feeling of pressure in the pelvis, and unusual or postmenopausal bleeding. Standard treatment for localised uterine sarcoma is surgery, which can include removal of the uterus and the cervix. It is not clear if removing both ovaries and both fallopian tubes has any benefit. Other approaches may include radiotherapy, chemotherapy, hormonal therapy, and simple observation with no additional intervention. The choice of the best approach depends on the specific subtype of uterine sarcoma, on the grade and on the extent of the disease.

Desmoid-type fibromatosis
Desmoid tumour (also called deep or aggressive fibromatosis) arises from fibroblasts, a type of cells that play a critical role in wound healing and in the structure of vital organs. Desmoid tumours can develop in any part of the body. Superficial desmoid tumours usually present as a painless or slightly painful lump whereas desmoid tumours inside the abdomen can cause severe pain, rupture or compression of organs, or bleeding.
Desmoid tumours can be indolent and have periods of stability and temporary regression or can be extremely aggressive. They never metastasise and if slow growing they need to be carefully watched by a medical oncologist.
Given the very slow growth of these tumours, a watchful waiting strategy may be the best option. In case of progression of the tumour, optimal treatment may consist of surgery, radiation therapy, chemotherapy, or hormonal therapy.

Breast sarcoma
Breast sarcomas arise from the connective tissue within the breast. They can be primary or secondary tumours. Primary tumours develop with no clear cause whereas secondary tumours develop after radiotherapy or as a consequence of chronic lymphoedema of the arm or of the breast after treatment for another malignancy. A specific type of breast sarcoma is angiosarcoma, which develops in the blood vessels or lymph vessels. Angiosarcomas are usually more aggressive than the other types of breast sarcomas such as phyllodes tumours and carcinosarcomas.
Patients with breast sarcoma should be treated in centres with experience in breast sarcomas. Surgery is the most important treatment option for breast sarcomas. The type of surgery may include wide local excision or mastectomy (surgery to remove the whole breast). The wide excision, which may be considered for smaller, low-grade breast sarcomas, removes the tumour and extra tissues to help reduce the chance of recurrence. Radiation therapy or chemotherapy may be recommended if the tumour is very large or is known to have spread outside of the breast or to reduce the risk of spreading.

 

What are the possible side effects of the treatments?

 

Risks and side effects of surgery
 

General risk of surgery

Minor surgery and biopsies usually pose less risk than major surgery: pain, infections at the site of surgery and reaction to the local anaesthesia are possible.

Risks in major surgical interventions are shared by all surgical interventions performed under general anaesthesia. These complications are infrequent and include deep vein thrombosis, heart or breathing problems, bleeding, infection, or reaction to the anaesthesia. Although there are risks, doctors will take the most appropriate steps to minimise them. Before any surgery, you should be clearly and carefully informed by the hospital about the risks.
 

Resection of a tumour in the arm or leg

After your operation you may have a tube in the wound to remove any fluid that collects in the area of the operation; the drainage tube will be removed once fluid has stopped draining. Immediately after surgery, your pain will usually be controlled either by an epidural or an intravenous continuous dose of painkillers administered with the aid of an electronic pump.

The consequences of the surgical resection depend on the extent of the resection. It is not always possible to preserve the entire limb and occasionally amputation of a part of the limb may be necessary.

  • Some people have a pain that appears to come from the part of the limb that has been amputated, known as phantom pain. It can be difficult to treat phantom limb pain and several types of treatment may be needed: anticonvulsants, antidepressants and opioids can help relieve pain from nerve damage or to attempt to block pain signals.
  • Rehabilitation begins shortly after surgery. The goal of rehabilitation is to help the patient return to the maximum level of function and independence possible, while improving the overall quality of life, physically, emotionally, and socially. The physiotherapist will show you how to do exercises to strengthen the trunk, arm, and leg muscles in order to prepare the remaining part of the limb for use of an artificial limb, called a prosthesis.

Resection of a tumour in the abdomen

Surgery of soft tissue sarcomas located within the abdomen may involve the removal of other organs or tissues (i.e. the kidney, the spleen, the pancreas, or part of the bowel). Your doctor should help you to find out how the treatment will influence daily life.

Risks and side effects of radiotherapy

During radiotherapy, side effects may occur in organs that are directly targeted, but also in healthy organs that lie close to the region irradiated. Side effects may be more intense when radiotherapy is administered together with chemotherapy. Radiotherapy in addition to surgery may also increase the risk of surgical complications and may cause problems with wound healing. Major improvements in radiotherapy techniques and machines have been made during the last decades and severe side effects are now very rare.
Most side effects of radiotherapy disappear gradually once the course of treatment has ended. For some people, however, they may continue for weeks or even longer. The radiotherapist team will support you during this treatment period.
 

Immediate side effects

Since radiotherapy is a local treatment, its side effects are local too. The most frequent general side effects of radiotherapy are:

  • Skin reaction (redness, soreness or/and itchiness) after three to four weeks of having external radiotherapy, but they usually settle down two to four weeks after the treatment has finished. However, the treated area may remain slightly more pigmented than the surrounding skin.
  • Dysphagia or difficulty to swallow due to inflammation of the oesophagus is frequent during radiotherapy directed to the neck or chest areas.
  • Nausea and vomiting, diarrhoea: some people find that their treatment makes them feel sick; this is most common when the treatment area is near the stomach or bowel.
  • Hair loss can occur when the head is irradiated.
  • Fatigue: this is a common side effect and may continue for some time after treatment finishes.
  • Sore mouth and oral mucositis: your mouth may become sore or dry, or you may notice small ulcers during this treatment; this is common when the treatment area is near the oral cavity. It’s very important to keep the oral mucosa well hydrated and your teeth clean during the course of the entire treatment.
     

Long-term side effects

It is rare to develop severe, long-term side effects after radiotherapy. However, long-term side effects can greatly affect the quality of life in some patients. Some possible long-term side effects are:

  • Long-term changes to the skin;
  • Occurrence of lymphoedema, a swelling that occurs when the lymph nodes and vessels are damaged by the radiotherapy;
  • Bowel incontinence, bladder incontinence, infertility and early menopause in women when pelvis is irradiated. If there is a risk of infertility following radiotherapy, your doctor will discuss all the options with you and suggest available support before your treatment. It may be possible for men to store sperm and women to store eggs for use in the future;
  • Neuropathic pain when major nerves are present in the radiated field.

Radiotherapy is associated with a slightly increased risk of developing a second tumour many years after the treatment. To reduce the risk, the type and the dose of the radiation therapy will be carefully planned.

Risks and side effects of chemotherapy

Side effects of chemotherapy are frequent, even if progress has been made in managing them using adequate supportive measures. They will depend on the drugs administered, on the doses, and on individual factors. If a patient has suffered from other medical problems in the past, some precautions should be taken and/or adaptation of the treatment should be made. Please tell your health care team about your previous experiences.
Listed below are the side effects that are known to occur with one or several of the chemotherapy drugs currently used for sarcomas. The nature, frequency and severity of the side effects vary for every chemotherapeutic drug combination used.

The most frequent general side effects of chemotherapy are:

  • Risk of infection: chemotherapy works by interfering with the cell's ability to grow or reproduce and can reduce the number of white blood cells, which help fight infection, a condition known as neutropenia. A blood test will be performed before having chemotherapy to check the number of white blood cells.
  • Bleeding: chemotherapy can reduce the number of platelets, which helps the blood to clot. Sometimes a platelet transfusion is needed if your platelet count is low.
  • Anaemia: chemotherapy can reduce the number of red blood cells, this may make you feel tired and breathless. A blood transfusion may be needed if your red blood cells count is low.
  • Nausea and vomiting: effective antiemetic drugs can be used to prevent, or reduce them.
  • Sore mouth: your mouth may become sore or dry, or you may notice small ulcers during treatment. Drinking plenty of fluids and cleaning your teeth regularly can help to reduce the risk of ulcers or mucositis.
  • Hair loss: not all chemotherapy drugs cause hair loss; hair may be lost completely or may just thin. If your hair does fall out, it will almost always grow back over a period of 3-6 months once the chemotherapy has finished.
  • Fatigue: feeling tired is a common side effect of chemotherapy.
  • Fertility: as there is a risk of infertility, your doctor will discuss with you all the options and available support before your treatment.

A local reaction may happen at place of insertion into the vein but also the local tissue might be damaged if drug leaks from the vein.

More specific side effects may occur depending on the specific chemotherapy drugs used. Not all available chemotherapy drugs will be used during the course of your disease. The choice will depend on the type of soft-tissue sarcoma and therefore, a profile of side effects will depend on specific drug(s) used. It is important that the health care team inform you upfront about the specific side effects that could be expected from the drugs you will receive.

  • For instance, with doxorubicin and epirubicin, urine may turn red or orange for a few days after treatment. It is important to know as this is not blood and is only due to the colour of the medication and should therefore not worry you.
  • Doxorubicin and epirubicin can cause damage to the heart muscle, therefore the assessment of heart function is important before therapy with these two drugs; the chance of heart problems depends on the dose of this drug and the patient’s condition. Heart problems may happen even if the patient does not have any risk factors. These drugs can make the skin more sensitive to sunlight and cause redness in areas where the patient has had radiotherapy in the past. The urine may turn red or orange for a few days after treatment. This is not blood and is only due to the colour of the medication.
  • Ifosfamide may cause kidney problems in some patients with blood in the urine and bladder pain. In some cases, it may also cause neurotoxicity with sleepiness, hallucinations, and confusion.
  • Docetaxel may cause swelling or fluid retention. It can sometimes cause temporary nail discoloration and an itchy skin rash. Severe allergic reactions are possible with docetaxel during the first or second infusion.
  • Gemcitabine may cause lung problems with trouble breathing, which can happen up to two weeks after discontinuation of the drug. Gemcitabine may cause flu-like symptoms such as feeling hot or cold and/or shivery and having a headache.
  • Vinorelbine may cause numbness or tingling in the fingers or toes, a condition known as peripheral neuropathy.
  • Vincristine may cause constipation or abdominal cramping, numbness or tingling in the fingers or toes.
  • Dacarbazine may cause an alteration of liver function. Dacarbazine may irritate the vein and may burn the skin if the drug leaks from the vein when it is given; tell your doctor if you have any redness, burning, pain, swelling, or leaking of fluid where the drug is going into your body.
  • Cisplatin can cause damage to the kidneys. Therefore, blood tests will be done before and during treatment to check renal function. Extra fluids through a drip before and after chemotherapy will be given intravenously to help protect your kidneys.
  • Cyclophosphamide may cause bladder damage with bladder irritation causing discomfort when passing urine. Treatment can affect kidneys and liver functions but this is usually mild and goes back to normal after treatment. At high doses, cyclophosphamide can cause damage to the lungs or the heart. Development of a second cancer is a rare side effect.
  • Trabectedin may cause tissue damage if the drug leaks from the vein. It may also affect liver and kidneys functions and sometimes cause pain in the joints or muscles for a few days after chemotherapy. Another potential side effect is deep vein thrombosis.

Tell your doctor about the symptoms you experienced, like rash, itching, shortness of breath, wheezing, cough, swelling of face, lips, tongue, throat, or any other signs.

Risks and side effects of targeted therapy

Pazopanib and imatinib are the only targeted therapies approved for the medical treatment of soft tissue sarcomas.
The main side effects of pazopanib include oedema (legs, arms, and face), wound healing problems, high blood pressure, diarrhoea, fatigue, abnormal liver function (often noticed by elevation of liver enzymes measured on blood tests), coagulation disorders (bleeding and clotting) and hair modification.

Imatinib may cause dizziness, diarrhoea, nausea and vomiting, muscle cramps, bleeding problems, blurred vision, oedema, most frequently around the eyes or in the legs and numbness or tingling in the hands, feet, or lips. Imatinib can also cause neutropenia, reducing the number of white blood cells, which help to fight infections.
Most of these side effects can be treated with appropriate medications or dose adjustments; therefore it is very important to tell your doctor about any discomfort you feel.

 

How can patient support groups help?

By Markus Wartenberg of the Sarcoma Patients EuroNet Association (www.sarcoma-patients.eu)

The day of the diagnosis. Whether it is a patient in the doctor's office, or a carer to hold a family member's hand or comfort a friend, a sarcoma diagnosis is a new, unplanned, and scary experience. Suddenly, there is a great deal to learn, understand, and cope with. But fortunately patients and caregivers are often not alone. There are people in the same situation who have never heard the word "sarcoma" before, who know what it's like to seek answers, to wait for results, to finally find THE right sarcoma expert, or to have to decide between therapy options.

In some European countries, patients with Sarcomas came together and founded patient support and advocacy groups. Mostly these are not-for-profit organisations founded by patients and their relatives - for patients. Their mission is to work together with leading sarcoma experts, the research industry, health insurance, other patient groups and other representatives of the healthcare system to optimize information, treatment and research situations for patients with a sarcoma, a GIST, a desmoid tumour or a specific type of bone cancer. The most important areas of their work are:

  • Improving the patient's level of information and competence (help them to help themselves)
  • Securing access to innovative therapies and improving the quality of treatment
  • Supporting sarcoma research
  • Advocating in the national health policy environment

Meanwhile, numerous studies show that timely treatment in interdisciplinary sarcoma centres significantly improves the results and prognoses among many patients. Hence, the international treatment guidelines (ESMO and NCCN) and the European sarcoma patients' organisations, which maintain that sarcoma - on account of its rarity - should be treated by experienced doctors and centres.

Unfortunately many patients with soft tissue sarcoma, spend a lot of time lost in the health-care system before getting in contact with experienced sarcoma experts. This much is painfully clear: had they been informed earlier of the existence of sarcoma centres, or if their doctors had referred them to these experts, their disease would have been diagnosed earlier, and they would have received better treatment. Several patients would have better prognoses today.

If a soft tissue sarcoma is suspected or concretely diagnosed, it may be useful to get a second opinion from another doctor before embarking on surgery or long-term, extensive treatment. In addition, it never hurts to seek independent, secondary findings, such as in an experienced sarcoma centre, if the patient has reasonable doubts about the initial diagnosis and/or does not feel well-advised. A second opinion can exclude the possibility of misdiagnoses, check over therapy options, and possibly introduce new/different treatment methods. Sarcoma patient support groups are very experienced when it comes to the national sarcoma expert landscape. They know very well where the sarcoma experts/centres are located in a country and they can help patients to find the best support for a second opinion, a very rare sarcoma subtype, for a special treatment option or a clinical study.

If a patient would like more information about her/his situation, or just needs someone to talk to, in could be extremely valuable to get in touch with a national sarcoma patient support group.

For a list of sarcoma support groups and charities in different countries, visit the Sarcoma Patients EuroNet Association’s group locator page at http://www.sarcoma-patients.eu.
 

What happens after the treatment?


Follow-up with doctors

Regardless of the goal of the therapy, after treatment, you will have regular follow-up appointments for several years. The usual practice will include a physical examination to look for any signs of cancer recurrence, and blood tests to check your general conditions and possible treatment side effects. Depending on primary localisation and sarcoma type, your doctor may ask for radiological examination of that area, as well as of areas where it can come back. This appointment is an important moment for you to talk about any new symptoms or changes you notice and any questions or problems you have.
At first, the appointments will be every few months. They will gradually become less frequent and the gap between them will get longer because the risk of the cancer coming back gets steadily lower over time. Generally, in high-risk soft tissue sarcomas it is expected that the recurrence appear in the first two to three years after treatment; low-risk sarcomas may relapse later, with lower odds.
The routine follow up depends on tumour grade, tumour size and tumour site. The optimal time schedule for routine follow-up is unknown, however the routine follow up after treatment for intermediate or high grade soft tissue sarcoma is more intensive than for low grade sarcoma.

Returning to normal life

Returning back to normal life is one of the main objectives in the treatment of soft tissue sarcomas. You are encouraged to tell your doctor about any worries, troubles or feelings about going home, or back to work or school. Make sure you discuss them with the health care team in advance so that help can be organised. Some patients may also find support from ex-patient groups or patient-targeted information media; additional expert psychological advice may be very useful.

What if the cancer comes back?

Soft tissue sarcomas can come back in the same area as the initial tumour. This is called a local recurrence. Patients with an isolated local recurrence may be offered surgery again to resect the tumour, but may also receive additional treatment.
Soft tissue sarcomas can also come back in organs and parts of the body other than the initial site. This process is called metastasis. In sarcoma patients, metastases mainly occur in the lungs, bone and liver. Since metastases, especially at early stage when they can be resected, may not cause any symptom, your doctor will pay specific attention to these sites during the follow-up. In patients previously treated with systemic drugs, further treatment lines with chemotherapy or targeted therapy may be considered.
Radiotherapy may be applied to relieve symptoms or prevent complications related to the tumour.
It is important that every tumour recurrence is evaluated by a multidisciplinary expert team, to select the most appropriate treatment modality or the most appropriate combination of treatments.

It may also happen, as a late effect of some therapies used for soft tissue sarcomas, that a new – secondary cancer appears. In case of suspicion for secondary cancer, your doctor will order a set of examinations to analyse the type of secondary cancer and its extent. Most appropriate options for management should be discussed within a multidisciplinary team, taking into consideration the previous treatments applied for soft tissue sarcoma.

 

Synonyms

Soft tissue cancer

Soft tissue sarcoma

Soft tissue tumour

Soft tissue tumor

Cancer of the soft tissue

Tumor of the soft tissue

Tumour of the soft tissue

Leiomyosarcoma

Rhabdomyosarcoma

Liposarcoma

Histiocytofibrosarcoma

Cancer of the muscle

Tumour of the muscle

Tumor of the muscle

Muscle cancer

Muscle tumour

Muscle tumor

Therapies by type

The following list of treatments is based on what we have found in scientific studies about cancer. More information about the listed therapies can be found under the tab THERAPIES. For registered drugs, radiotherapy and surgical interventions, approval by the authorities is given.

Surgical interventions

Procedures involving instrumental means to investigate or treat a cancer, or to improve the body’s functions or appearance. Generally, a surgical intervention involves an incision. More

Radiotherapy

Medical use of high-energy radiation to kill cancer cells and reduce tumor size. More

Registered drugs

Anti-cancer drugs with market authorization in the USA or in countries of the European Union. More

Energy based therapies

Use of electromagnetic energy including electricity, magnetic fields, radio waves, microwaves, infrared rays and light to diagnose or treat disease.

Clinical trials

A clinical trial is a research study conducted with patients to evaluate whether a new treatment is safe (safety) and whether it works (efficacy). Clinical trials are performed to test the efficacy of drugs but also non-drug treatments such as radiotherapy or surgery and combinations of different treatments. Clinical trials take place in all kinds of hospitals and clinics, but mostly in academic hospitals. They are organized by researchers and doctors.

The Anticancer Fund provides a tool to search for phase III clinical trials by type of cancer and by country. For Belgium, the Netherlands, Switzerland, Luxembourg, France and the UK, the Anticancer Fund provides contacts to get more information about the phase III clinical trials currently ongoing. Discuss the possibilities of participating in one of these clinical trials with your doctor.

The list of the phase III clinical trials for soft tissue cancer is available here.